The nature of anterograde and retrograde memory impairmentafter damage to the medial temporal lobe

Christine N. Smith a,b, Jennifer C. Frascino a,b, Ramona O. Hopkins c,d, Larry R. Squire b,e,n

a Department of Psychiatry, University of California, San Diego, CA 92093, USAb Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USAc Department of Psychology and Neuroscience Center, Brigham Young University, Provo, UT 84143, USAd Department of Medicine, Pulmonary and Critical Care Division, Intermountain Medical Center, Murray, UT 84143, USAe Departments of Psychiatry, Neurosciences, and Psychology, University of California, San Diego, La Jolla, CA 92093, USA

a r t i c l e i n f o

Article history:Received 7 June 2013Received in revised form3 September 2013Accepted 5 September 2013Available online 14 September 2013

Keywords:Anterograde amnesiaRetrograde amnesiaMemoryMedial temporal lobe

a b s t r a c t

The study of anterograde and retrograde amnesia (AA and RA) in the laboratory and the clinic hasprovided important information about the structure and organization of memory. The severity of AA isusually correlated with the severity of RA. Nevertheless, variations in the expression of AA and RA havebeen reported, which presumably reflect variation in the locus and extent of brain damage. Therelationship between AA and RA has rarely been described quantitatively in groups of patients wheredetailed anatomical information is available. We have quantified the severity of AA and RA for factualinformation in 11 memory-impaired patients with bilateral medial temporal lobe lesions, including 5 forwhom detailed post-mortem neurohistological information was available. The findings describe anorderly relationship between AA and RA, such that patients with more severe AA also had moreextensive RA. In addition, RA was measurable only after AA reached a substantial level of severity. Thisrelationship between AA and RA in patients with identified medial temporal lobe lesions appears todescribe a general principle, which applies to a range of etiologies, including traumatic amnesia, wherethe locus and extent of brain damage is less well understood. Whenever patients deviate substantiallyfrom the relationship described here, one should be alert to the likelihood that significant damage hasoccurred outside or in addition to the structures in the medial temporal lobe.

Published by Elsevier Ltd.

1. Introduction

The phenomena of anterograde and retrograde amnesia havebeen described in the laboratory and clinic for more than 100years (Ribot, 1881) and have been an important source of informa-tion about the structure and organization of memory. Anterogradeamnesia (AA) refers to an impaired capacity for new learning.Retrograde amnesia (RA) refers to the loss of information that wasacquired before the onset of amnesia. It has long been recognizedthat AA and RA tend to occur together in the same patients(Barbizet, 1970; Rose & Symonds, 1960; Russell, 1971; Victor,1969). In addition, the severity of AA is usually correlated withthe severity of RA (Kopelman, 1989; Squire & Alvarez, 1995;Wickelgren, 1979). Yet it is also true that RA can sometimes appeardisproportionately severe in comparison to AA (Barr, Goldberg,Wasserstein, & Novelly, 1990; Bright et al., 2006; Hornberger et al.,2010; Kapur, Ellison, Smith, McLellan, & Burrows, 1992; Milton

et al., 2010; O'Connor, Butters, Miliotis, Eslinger, & Cermak, 1992;Reed & Squire, 1998; Sehm et al., 2011). Moreover, AA can some-times occur in the absence of RA (Corkin, Hurt, Twitchell, Franklin,& Yin, 1987; Russell & Nathan, 1946). These examples illustratevariations in the expression of AA and RA, which presumablydepend on the locus and extent of brain injury or disease. Detailedneuroanatomical information should clarify the relationshipbetween AA and RA.

The most comprehensive study of the relationship between AAand RA was carried out in more than 1000 patients who hadsustained closed head injury (Russell & Nathan, 1946). Fig. 1 showsthe relationship between the duration of post-traumatic amnesiaand the extent of RA for 972 cases. RA was assessed informally,usually by querying about autobiographical information. We takethe duration of AA to be indicated by the time after injury whenpost-traumatic amnesia resolves. As the duration of AA increased,the number of cases exhibiting pronounced RA also increased.Interestingly, when AA covered one day or less, only a smallnumber of cases (N¼19) exhibited substantial RA (Russell &Nathan, 1946; Table 4a). In fact, out of the 503 cases exhibitingAA of one day or less, 32 had no RA at all. These data describe an

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n Corresponding author. Tel.: þ1 858 642 3628; fax: þ1 858 552 7457.E-mail address: lsquire@ucsd.edu (L.R. Squire).

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orderly relationship between AA and RA and also suggest that AAmay need to reach some threshold of severity before RA isobserved. Put differently, it appears to be easier to disrupt newlearning ability and harder to disrupt already acquired informa-tion, presumably because some fixation or consolidation of mem-ory has occurred (McGaugh, 2000; Squire & Alvarez, 1995).Unfortunately, in cases of (non-penetrating) traumatic braininjury, the locus and extent of damage is often difficult todetermine. In patient groups with identified neuroanatomicalchange, little information is available about how the severity ofAA relates to the severity of RA.

To obtain quantitative information about AA and RA in patientswith identified neuropathological change, we have determined theseverity of AA and RA in 11 memory-impaired patients with identifiedbilateral lesions within the medial temporal lobe. For five of thepatients, detailed post-mortem neurohistological information wasavailable. Patients were assessed with five measures of AA and onemeasure of RA. The AA measures assessed both verbal and nonverballearning ability. For measures of RA, we considered using either testsof autobiographical information or tests of factual information.

Whereas early studies of RA depended on informal interviews thatfocused on autobiographical information, beginning in the 1970smethods were developed to assess RA quantitatively by asking factualquestions about news events or famous persons from different pasttime periods (Albert, Butters, & Levin, 1979; Marslen-Wilson & Teuber,1975; Sanders & Warrington, 1971). Quantitative assessments ofautobiographical memory were also subsequently developed (Crovitz& Schiffman, 1974; Kopelman, Wilson, & Baddeley, 1989), but these donot easily achieve the kind of temporal resolution that is afforded, forexample, by news events tests. Accordingly, to explore the quantitativerelationship between AA and RA, we assessed RA with a test ofapproximately 100 news events that covered most of the life spanprior to the onset of amnesia.

2. Materials and methods

2.1. Participants

Data are presented for eleven memory-impaired patients with damage limitedto the MTL (Table 1). For the first five patients described below, the description ofdamage was based on post-mortem neurohistological analysis. Patient RB becameamnesic in 1978 at age 52 as the result of an ischemic event that occurred as acomplication of open heart surgery. After his death in 1983, he was found to havebilateral damage limited to the CA1 field of the hippocampus (Zola-Morgan, Squire,& Amaral, 1986). Patient GD became amnesic in 1983 at age 43 following a period ofhypotension that occurred during major surgery. After his death in 1992, he wasalso found to have bilateral damage limited to the CA1 field of the hippocampus(Rempel-Clower, Zola, Squire, & Amaral, 1996). Patient WH became amnesic in 1986at age 57 possibly due to cerebral ischemia. After his death in 1993, he was found tohave bilateral damage involving all fields of the hippocampus as well as damage tothe dentate gyrus, subiculum, and some of entorhinal cortex (Rempel-Clower et al.,1996). Patient LM became amnesic in 1984 at age 54 as the result of respiratorydistress that occurred during an epileptic seizure. After his death in 1990 he wasfound to have bilateral damage involving all fields of the hippocampus as well asdamage to the dentate gyrus (Rempel-Clower et al., 1996). Patient EP becameamnesic in 1992 at age 70 after contracting viral encephalitis. After his death in2008, he was found to have large, bilaterally symmetric lesions of the MTL thateliminated the temporal pole, the amygdala, the entorhinal cortex, the hippocam-pus, the perirhinal cortex, and rostral parahippocampal cortex. His lesion alsoextended laterally to substantially involve the fusiform gyrus. Perhaps because ofloss of connectivity between medial and lateral structures, there were secondarychanges in the superior, middle, and temporal gyri, which were atrophic, and theunderlying white matter was gliotic (Insausti, Annese, Amaral, & Squire, 2013).

Of the remaining six patients, five have damage thought to be limited to thehippocampus (CA fields, dentate gyrus, and subicular complex), and one has largebilateral lesions of the MTL. Patient KE became amnesic in 2004 at age 63 after anepisode of ischemia associated with kidney failure and toxic shock syndrome. LJ(the only female) became amnesic at age 51 during a 6-month period in 1988 withno known precipitating event. Her memory impairment has been stable since thattime. Patient GP became amnesic in 1987 at age 41 after contracting viral

Fig. 1. The relationship between the duration of anterograde amnesia (AA) and theseverity of retrograde amnesia (RA) in 972 cases of traumatic brain injury. Note theorderly relationship between AA and RA. Data from Russell and Nathan (1946);Table 4. We have considered the duration of AA to be the time after injury whenpost-traumatic amnesia resolves.

Table 1Characteristics of memory-impaired patients.

Patient Sex Age (yr) Education (yr) Anatomical findings IQ (WAIS-R) WMS-R

Attention Verbal Visual General Delay

RB M 53 10 Hn 103 – – – – –GD M 45 12 Hn 92 109 86 88 85 60WH M 64 17 H 113 88 72 82 67 o50LM M 55 15 H 109 124 94 82 89 62EP M 79 12 MTL 98 94 59 92 68 56KE M 64 13.5 H 108 114 64 84 72 55LJ F 68 12 H 101 104 85 87 81 54GP M 57 16 MTL 98 102 79 62 66 o50RS M 49 12 H 99 99 85 81 82 o50GW M 46 12 H 108 105 67 86 70 o50JRW M 42 12 H 90 87 65 95 70 o50

Note: The Wechsler adult intelligence scale-revised (WAIS-R) and the Wechsler memory-scale revised (WMS-R) yield mean scores of 100 in the normal population, with a SDof 15. The WMS-R does not provide numerical scores for individuals who score o50. KE, LJ, EP, GP, and GWwere given the WAIS-III rather than the WAIS-R. RB was not giventhe WMS-R. Age indicates the age of the patient when given the news events test. Neurohistological information is available for the first five patients listed. Asterisk indicatesa lesion limited to the CA1 field of the hippocampus. H, bilateral damage to the hippocampus with minimal damage to adjacent cortex; MTL, bilateral damage to thehippocampus and parahippocampal gyrus; IQ, intelligence quotient.

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encephalitis. Patients RS and GW became amnesic in 1998 and 2001, respectively(ages 41 and 42), after drug overdoses and associated respiratory failure. PatientJRW became amnesic in 1990 at age 27 following an anoxic episode associated withcardiac arrest.

Estimates of MTL damage for these six patients were based on magneticresonance images from 19 age-matched, healthy males for KE, GP, RS, GW, and JRW,and 11 age-matched, healthy females for patient LJ (Gold & Squire, 2005). PatientsKE, LJ, RS, GW, and JRW have an average bilateral reduction in hippocampal volumeof 49, 46, 33, 48 and 44% respectively (all values42.9 SDs from the control mean).On the basis of patients LM and WH, who had similar bilateral volume loss in thehippocampus (estimated from magnetic resonance images) and for whom detailedpostmortem neurohistological information was obtained (Rempel-Clower et al.,1996), the degree of volume loss in these five patients likely reflects nearlycomplete loss of hippocampal neurons. For these same five patients, the volumeof the parahippocampal gyrus (temporopolar, perirhinal, entorhinal, and parahip-pocampal cortices) is reduced by 11, �5, 10, 12 and �17%, respectively (all valueswithin 2 SDs of the control mean). The post-encephalitic patient GP has a 96%reduction in hippocampal volume bilaterally and a 94% reduction in parahippo-campal gyrus volume. Eight coronal magnetic resonance images from each of thesepatients, together with detailed descriptions of the lesions, can be found inSupplementary material. The volumes for parahippocampal gyrus differ a littlefrom volumes reported previously for these patients and are based on recentlypublished, more detailed guidelines for identifying the caudal border of the gyrus(Franko, Insausti, Artacho-Perula, Insausti, & Chavoix, 2012).

Additional measurements, based on four controls for each patient, were carriedout for the frontal lobes, lateral temporal lobes, parietal lobes, occipital lobes,insular cortex, and fusiform gyrus (see Bayley, Gold, Hopkins, & Squire, 2005). Forpatients KE, LJ, RS, GW, and JRW, volumes of these regions are within 16% of controlvalues. The only volume reduction greater than 1.3 SDs of the control mean was theparietal lobe for RS (Bayley et al., 2005). For patient GP, the volumes of the insularcortex and the fusiform gyrus were reduced bilaterally by 65% and 49%,respectively.

Forty-two healthy volunteers served as controls for the news events test (12female, 60.471.8 years of age, 13.670.5 years of education; means7SEMs).Eleven of these also served as controls for four of the anterograde memory tests(2 female, 61.373.3 years of age, 15.771.1 years of education; means7SEMs).A separate group of eight volunteers (Squire & Shimamura, 1986) served as controlsfor one anterograde memory test: Rey Auditory Verbal Learning Test (5 female,50.971.2 years of age, 14.870.7 years of education; means7SEMs). All proce-dures were approved by the Institutional Review Board at the University ofCalifornia San Diego. Participants gave written informed consent prior to participa-tion in accordance with the Declaration of Helsinki.

2.2. Measuring anterograde amnesia

2.2.1. Delayed recall of a complex figureParticipants copied a complex diagram (Rey-Osterrieth figure; Osterrieth, 1944)

and then reproduced it from memory after a 10–15 min delay. The copy and thereproduction of the figure were each scored on a 36-point scale (Taylor, 1998).

2.2.2. Paired-associate learningParticipants completed three study-test trials with a list of 10 unrelated word

pairs (Squire & Shimamura, 1986). To begin, the word pairs were displayed one at atime while the experimenter read each pair aloud. Immediately after all 10 pairswere presented, participants were shown the first word from each pair and askedto recall the second word. This procedure was repeated two more times with thesame pairs in different orders, and the score was the total number of pairs recalled(maximum¼30).

2.2.3. Rey auditory verbal learning test (RAVLT)For the recall portion of the RAVLT, 15 words were presented orally, and then

recall was tested. The study-test sequence was then repeated four times. Therecognition portion of the test used 15 different words. Five successive study-testtrials were given, and testing on each trial followed a yes-no format with 30 words(15 old 15 new). The score was the average percent correct score across all 10 trials.RB was not given this test.

2.2.4. Dementia rating scaleParticipants were administered the memory subscale from the dementia rating

scale (Mattis, 1976). The maximum score is 25 points. RB was not given this test.

2.2.5. Wechsler memory scale-revised (WMS-R) logical memory subtestRecall was tested for two short prose passages, each consisting of 25 segments.

The first passage was read aloud to the participant, followed by an immediate recalltest. The second passage was then read aloud, also followed by an immediate recalltest. Recall of both passages was then tested 30 min later. The score was the sum ofsegments recalled from both passages at the 30-min test. Patient RB received theWMS rather than the WMS-R.

Based on the performance of controls, z-scores were calculated for each patientfor each of the five anterograde memory tests. The five z-scores were then averagedto create a measure of AA for each patient.

2.3. Measuring retrograde amnesia

News events test. The test was constructed from a pool of 289 questionscovering notable news events that occurred in a specific year between 1938 and2004. For each patient, the questions spanned from the onset of amnesia to thetime when the patient was 15 years old (mean¼105.0717.5 questions per patient).We did not query earlier time periods, because even for healthy individualsperformance is poor for news events that occurred during childhood or earlyadolescence (Squire, 1974). The news events test was administered in a free recallformat (e.g., What caused a suspension bridge to collapse over the Narrows atTacoma, Washington? [1940]; Who killed John Lennon? [1980], Who is ElizabethSmart? [2003], the year for each event was not included as part of the question).The score was the percentage of questions answered correctly from each 5-yeartime interval covered by the test-from the five years immediately preceding theonset of amnesia to the time when the patient was 15 years old. An average of 13.1questions (range 7.5 to 31.1 questions) was available for each 5-year time interval.

Eight to sixteen controls for each patient were identified from a pool of 42controls, based on age, education, and when they took the test relative to thepatient (within about 1 year). Some controls were matched to more than onepatient. For each control, the questions were assigned to 5-year time intervalsaccording to the time of onset of amnesia for the patient to whom the control wasmatched. The extent of RA for each patient was defined as the number of 5-yeartime intervals where the patient's score was significantly below the score of thecontrols for the same time interval (one-sample t-test). The AA and RA measureswere obtained at roughly similar times (mean¼2.870.9 years apart). This intervalwas calculated by averaging the dates when the five AA tests were given andsubtracting this value from the date when the RA test was given.

Data for patients and the news events test have been published previously in adifferent format (Bayley, Hopkins, & Squire, 2006; Squire, Haist, & Shimamura,1989; Zola-Morgan et al., 1986).

3. Results

Fig. 2 shows the severity of AA and RA for each patient. Acrossall 11 patients, there was a significant relationship between AAand RA (r¼0.81, po0.005), such that patients with more severeAA had more severe RA. Thus, when damage extended outside thehippocampus to substantially involve the parahippocampal gyrus(EP and GP), substantial RA was consistently observed, and AA was

Fig. 2. The relationship between the severity of anterograde amnesia (AA) and theseverity of retrograde amnesia (RA) in 11 patients with bilateral damage to themedial temporal lobe (r¼0.81, po0.005). Patients are represented by their initials(see Table 1). AA is the mean z-score from five tests of new learning ability (seeSection 2.2). RA was measured by a test of approximately 100 questions aboutnotable news events that covered most of the lifespan prior to the onset of amnesia.The extent of RA was measured in 5-year intervals (see Section 2.3).

C.N. Smith et al. / Neuropsychologia 51 (2013) 2709–27142711

very severe (z¼�6.7). Patient EP had the most severe AA and alsohad more RA than any other patient. Finally, when the lesion waslimited largely to the hippocampus, RA and AA were less severe(for AA, z¼�4.1).

We also estimated the severity of RA by calculating eachpatient's mean percent correct score across the entire test (insteadof calculating the number of 5-year time periods in which patientsobtained impaired scores). A significant relationship between AAand RA was found with this method (r¼0.73, po0.05; Fig. S2A).The relationship was also strong when the mean percent correctscores were converted to z-scores based on how many standarddeviations each patient's score fell below the control group's score(r¼0.79, po0.01; Fig. S2B).

It has been suggested that comparisons of AA and RA would beadvantaged by using the same kind of test to assess both AA andRA (Kopelman, 2000; Mayes, 2002; Mayes, Daum, Markowisch, &Sauter, 1997). Ten of the 11 patients in our study were tested notonly about news events that occurred before they became amnesicbut also about news events that occurred after they becameamnesic. For these patients a mean of 71.6 questions covered theperiod after they became amnesic. AA was estimated by calculat-ing a mean percent correct score for each patient. By this method,AA and RA were related (r¼0.73, po .05; Fig. S3A). A marginalrelationship between AA and RA was found when the percentcorrect scores were converted to z-scores (r¼0.59, po .08;Fig. S3B). The results of two additional analyses are illustrated inFig. S4A, B.

It is apparent in Fig. 1 that measurable RA was observed onlyafter AA reached a substantial level of severity. While RA coveringless than 5 years would not have been detected by our method,which depended on 5-year time intervals, the results indicatedthat RA does not typically reach back 5 years or more unless AA isquite severe. In addition, one should not conclude that patientswithout detectable RA (RB and GW) had no RA at all. Rather, RAmay not have covered a sufficient number of years in the mostrecent 5-year interval for impairment to be detected. In fact, GWdid exhibit two years of RA on the news events test when the5-year interval immediately prior to the onset of amnesia wasrescored year by year.

4. Discussion

We measured AA and RA in 11 patients with damage to theMTL. As the severity of AA increased, so did the severity of RA.Patients with damage to both the hippocampus and parahippo-campal gyrus exhibited the most severe AA and the most severeRA. Patients with damage limited largely to the hippocampusexhibited less severe AA and less severe RA. Although there wasvariability in the severity of RA, the average severity of RA in thetwo patient subgroups (mean¼10 years, median¼5 years forthe hippocampal group and mean¼35 years, median¼35 yearsfor the MTL group) are in line with previous reports (Bayley et al.,2006; Manns, Hopkins, & Squire, 2003).

Our findings for memory-impaired patients with bilateral MTLlesions parallel the findings from a large study of closed-headinjury (Russell & Nathan, 1946) as well as the findings from asmaller study of 25 patients (Blomert & Sisler, 1974). For all thesepatient groups the relationship between AA and RA was similar.RA was substantial only after a threshold of AA was reached(compare Figs. 1 and 2). In the case of our patients (Fig. 2), onecould wonder if RA might have been detected in association withless severe AA if the test of RA had been more sensitive (i.e., if ourtest could have detected an RA of less than five years). Yet, Russelland Nathan observed a threshold even when AA and RA weremeasured in minutes and days instead of years. For example, when

AA was 1 day or less, 6–10% of patients exhibited no RA at all(Russell & Nathan, 1946, Tables 4 and 5). Moreover, even when AAcovered more than 1 day, 27% of patients had RA of less than 1 min(Russell & Nathan, 1946, Table 5). Lastly, in the case of gunshotwounds to the head, 65 of 185 cases had a definite period of AAbut no RA at all (Russell & Nathan). Thus, anterograde memory iseasier to disrupt than retrograde memory, and this conclusiondoes not depend on the sensitivity of the measures.

All these studies found variable severity of RA in patients with asimilar severity of AA. For example, in our study RA ranged fromno RA to 15 years in patients with similar AA (GD, LM, RB, and RS).In the study of traumatic amnesia, RA ranged from 0 to 12 h whenAA was 1 day or less (Russell & Nathan, 1946, Tables 4 and 5). Inaddition, RA was consistently observed when AA was sufficientlysevere. [Note one report of traumatic amnesia (N¼109) that foundno relationship between AA and RA (Corkin et al., 1987), though inthis study patients with the mildest and most severe symptomswere excluded.]

Although patients with MTL lesions, as presented here, andpatients with traumatic amnesia provide the most completeinformation about the relationship between AA and RA, the factthat AA and RA are often associated has been noted in patientswith a range of etiologies. Thus, AA and RA have been described asappearing and then diminishing together (though not necessarilyat the same rate) in cases of transient global amnesia (Evans, 1966;Fisher & Adams, 1964; Kritchevsky & Squire, 1989; Shuttleworth &Morris, 1966), Wernicke's encephalopathy/Korsakoff's psychosis(Victor, Adams, & Collins, 1989), tumors or cysts near the thirdventricle (Ignelzi & Squire, 1976; Victor, 1969), electroconvulsivetherapy (Squire & Chace, 1975; Squire, Slater, & Miller, 1981), andtransient epileptic amnesia (Zeman, Boniface, & Hodges, 1998).Note that interpretation of remote memory performance intransient epileptic amnesia can be complicated by the fact thatpoor memory performance (particularly for recent time periods)may result from impaired new learning (secondary to seizures) aswell as from retrograde memory loss itself (Butler & Zeman, 2008;Hornberger et al., 2010). Note too that this association between AAand RA need not hold in all circumstances, for example, inKorsakoff's syndrome (Fama, Marsh, & Sullivan, 2004; Mayeset al., 1997), when remote memory impairment can be extensiveand its severity related in part to abnormalities in neocortex (Famaet al., 2004), rather than the MTL.

It is worth mentioning that in some of these studies, and in thework by Russell and Nathan (1946) RA was assessed with mea-sures of autobiographical memory. Our study assessed RA bytesting semantic memory for public events, so that our conclusionsabout the relationship between AA, RA, and MTL damage arelimited to non-autobiographical material. It would be useful tostudy the relationship between AA and RA in patients with medialtemporal lobe damage using tests of autobiographical memory.Unfortunately, the tools available to measure autobiographicalmemory do not easily lend themselves to such an analysis.Specifically, most of the tests (Kopelman et al., 1989; Levine,Svoboda, Hay, Winocur, & Moscovitch, 2002) sample only a fewtime periods. Better tests could be constructed [see Bayley,Hopkins, and Squire (2003) for use of the method introduced byCrovitz and Schiffman (1974)], but even then it would be difficultto achieve good temporal resolution across the life span.

Patient EP had the most severe AA and the most severe RA,which covered as much as 50 years prior to the onset of hisamnesia (Fig. 2). Nonetheless, his performance improved some-what when questions concerned events that had occurred 430years before his amnesia and reached normal levels for the period46–50 years before amnesia when he was 20–24 years old.Although EP's score for RA did fall within the 95% confidenceinterval of the regression line (even when his data were not used

C.N. Smith et al. / Neuropsychologia 51 (2013) 2709–27142712

to construct the regression line), he differed from the otherpatients in that his neuropathology extended into lateral temporalcortex. These changes appeared to be secondary to the primaryfocus of his encephalitic lesion (Insausti et al., 2013). Accordingly itis possible that these changes in lateral temporal cortex madesome contribution to the extent and severity of his retrogradememory loss.

Lateral temporal cortex is essential for long-established semanticknowledge about objects and word meanings (Hodges & Graham,2001; Hodges, Patterson, Oxbury, & Funnell, 1992; Levy, Bayley, &Squire, 2004). Damage to this region has also been associated withcases where RA is disproportionately severe in comparison to AA(Barr et al., 1990; Bright et al., 2006; O'Connor et al., 1992; Reed &Squire, 1998). Particularly notable are cases of what has been termedfocal retrograde amnesia (Hornberger et al., 2010; Kapur, 1993; Kapuret al., 1992; Kopelman, 2000; Sehm et al., 2011). [Note that it can bedifficult to distinguish focal retrograde amnesia from psychogenicamnesia (Kopelman, 2000; Markowitsch, 2002)].

In summary, we examined the relationship between AA and RAfor factual information in patients with MTL lesions wheredetailed anatomical information was available. There was anorderly relationship between the severity of AA and the extentof RA. A similar relationship between AA and RA appears to hold inthe case of patients with a range of etiologies where the locus andextent of brain injury is less well understood. In these cases [forexample, in patients with traumatic amnesia from closed headinjury (Russell & Nathan, 1946)], we suggest that significantdysfunction has occurred within the MTL. Similarly, for new cases,one might propose that, when AA and RA scores are in a similarrelationship to what we report here, significant damage hasoccurred within the MTL. Furthermore, when patients have AAand RA scores that deviate substantially from the relationshipdescribed here, one should be alert to the likelihood that sig-nificant damage has occurred outside of or in addition to struc-tures in the MTL.

Acknowledgments

We thank Ashley Knutson and Erin Light for assistance. Thiswork was supported by the Medical Research Service of theDepartment of Veterans Affairs (VA Merit to L.R.S.), NationalInstitute of Mental Health (MH24600 to L.R.S.), and a NationalScience Foundation grant (#SMA-1041755) to the TemporalDynamics of Learning Center, an NSF Science of Learning Center.

Appendix A. Supplementary Material

Supplementary data associated with this article can be found inthe online version at http://dx.doi.org/10.1016/j.neuropsychologia.2013.09.015.

References

Albert, M. S., Butters, N., & Levin, J. (1979). Temporal gradients in the retrograde amnesiaof patients with alcoholic Korsakoff's disease. Archives of Neurology, 36, 211–216.

Barbizet, J. (1970). Human memory and its pathology. San Francisco: W.H. Freemanand Co.

Barr, W. B., Goldberg, E., Wasserstein, J., & Novelly, R. A. (1990). Retrograde amnesiafollowing unilateral temporal lobectomy. Neuropsychologia, 28, 243–256.

Bayley, P. J., Hopkins, R. O., & Squire, L. R. (2003). Successful recollection of remoteautobiographical memories by amnesic patients with medial temporal lobelesions. Neuron, 38(1), 135–144.

Bayley, P. J., Gold, J. J., Hopkins, R. O., & Squire, L. R. (2005). The neuroanatomy ofremote memory. Neuron, 46(5), 799–810.

Bayley, P. J., Hopkins, R. O., & Squire, L. R. (2006). The fate of old memories aftermedial temporal lobe damage. Journal of Neuroscience, 26(51), 13311–13317.

Blomert, D. M., & Sisler, G. C. (1974). Measurement of retrograde post-traumaticamnesia. Canadian Psychiatric Association Journal, 19(2), 185–192.

Bright, P., Buckman, J. R., Fradera, A., Yoshimasu, H., Colchester, A. C. F., & Kopelman,M. D. (2006). Retrograde amnesia in patients with hippocampal, medialtemporal, temporal lobe, or frontal pathology. Learning & Memory, 13, 545–557.

Butler, C. R., & Zeman, A. Z. (2008). Recent insights into the impairment of memoryin epilepsy: Transient epileptic amnesia, accelerated long-term forgetting andremote memory impairment. Brain: A Journal of Neurology, 131(Pt 9),2243–2263.

Corkin, S., Hurt, R. D., Twitchell, T. E., Franklin, L. C., & Yin, R. K. (1987).Consequences of nonpenetrating and penetrating head injury: Retrogradeamnesia, post-traumatic amnesia, and lasting effects on cognition. In: H.S. Levin, J. Grafman, & H. M. Eisenberg (Eds.), Neurobehavioral recovery fromhead injury (pp. 318–329). New York: Oxford University Press.

Crovitz, H. F., & Schiffman, H. (1974). Frequency of episodic memories as a functionof their age. Bulletin of the Psychonomic Society, 4, 517–518.

Evans, J. H. (1966). Transient loss of memory, an organic mental syndrome. Brain,89, 539–548.

Fama, R., Marsh, L., & Sullivan, E. V. (2004). Dissociation of remote and anterogradememory impairment and neural correlates in alcoholic Korsakoff syndrome.Journal of the International Neuropsychological Society: JINS, 10(3), 427–441.

Fisher, C. M., & Adams, R. D. (1964). Transient global amnesia. Acta NeurologicaScandinavica. Supplementum, 40(Suppl. 9), 1–83.

Franko, E., Insausti, A. M., Artacho-Perula, E., Insausti, R., & Chavoix, C. (2012). epub.(2012). Identification of the human medial temporal lobe regions on magneticresonance images. Human Brain Mapping, http://dx.doi.org/10.1002/hbm.22170.

Gold, J. J., & Squire, L. R. (2005). Quantifying medial temporal lobe damage inmemory-impaired patients. Hippocampus, 15(1), 79–85.

Hodges, J. R., & Graham, K. S. (2001). Episodic memory: Insights from semanticdementia. Philosophical Transactions Royal Society of London Series, B356(356),1423–1434.

Hodges, J. R., Patterson, K., Oxbury, S., & Funnell, E. (1992). Semantic dementia:Progressive fluent aphasia withtemporal lobe atrophy. Brain, 115, 1783–1806.

Hornberger, M., Mohamed, A., Miller, L., Watson, J., Thayer, Z., & Hodges, J. R. (2010).Focal retrograde amnesia: Extending the clinical syndrome of transientepileptic amnesia. Journal of Clinical Neuroscience: Official Journal of theNeurosurgical Society of Australasia, 17(10), 1319–1321.

Ignelzi, R. J., & Squire, L. R. (1976). Recovery from anterograde and retrogradeamnesia after percutaneous drainage of a cystic craniopharyngioma. Journal ofNeurology, Neurosurgery, and Psychiatry, 39(12), 1231–1235.

Insausti, R., Annese, J., Amaral, D. G., & Squire, L. R. (2013). Human amnesia and themedial temporal lobe illuminated by neuropsychological and neurohistologicalfindings for patient E.P. Proceedings of the National Academy of Sciences of theUnited States of America, 110(21), E1953–E1962.

Kapur, N. (1993). Focal retrograde amnesia in neurological disease: A criticalreview. Cortex, 29, 217–234.

Kapur, N., Ellison, D., Smith, M. P., McLellan, D. L., & Burrows, E. H. (1992). Focalretrograde amnesia following bilateral temporal lobe pathology. Brain, 115, 73–85.

Kopelman, M. D. (1989). Remote and autobiographical memory, temporal contextmemory and frontal atrophy in Korsakoff and Alzheimer patients. Neuropsy-chologia, 27, 437–460.

Kopelman, M. D. (2000). Focal retrograde amnesia and the attribution of causality:An exceptionally critical review. Cognitive Neuropsychology, 17(7), 585–621.

Kopelman, M. D., Wilson, B. A., & Baddeley, A. D. (1989). The autobiographicalmemory interview: A new assessment of autobiographical and personalsemantic memory in amnesic patients. Journal of Clinical and ExperimentalNeuropsychology, 5, 724–744.

Kritchevsky, M., & Squire, L. R. (1989). Transient global amnesia: Evidence forextensive, temporally-graded retrograde amnesia. Neurology, 39, 213–218.

Levine, B., Svoboda, E., Hay, J. F., Winocur, G., & Moscovitch, M. (2002). Aging andautobiographical memory: Dissociating episodic from semantic retrieval. Psy-chology and Aging, 17(4), 677–689.

Levy, D. A., Bayley, P. J., & Squire, L. R. (2004). The anatomy of semantic knowledge:Medial vs. lateral temporal lobe. Proceedings of the National Academy of Sciencesof the United States of America, 101(17), 6710–6715.

Manns, J. R., Hopkins, R. O., & Squire, L. R. (2003). Semantic memory and the humanhippocampus. Neuron, 37, 127–133.

Markowitsch, H. J. (2002). Functional retrograde amnesia—Mnestic block syn-drome. Cortex, 38(4), 651–654.

Marslen-Wilson, W. D., & Teuber, H. L. (1975). Memory for remote events inanterograde amnesia: Recognition of public figures from news photographs.Neuropsychologia, 13, 353–364.

Mattis, S. (1976). Dementia rating scale. In: R. Bellack, & B. Keraso (Eds.), Geriatricpsychiatry X (pp. 77–121). New York: Grune and Stratton.

Mayes, A. R. (2002). Does focal retrograde amnesia exist and if so, what causes it?Cortex, 38(4), 670–673.

Mayes, A. R., Daum, I., Markowisch, H. J., & Sauter, B. (1997). The relationshipbetween retrograde and anterograde amnesia in patients with typical globalamnesia. Cortex, 33(2), 197–217.

McGaugh, J. L. (2000). Memory—A century of consolitation Science, 287, 248–251.Milton, F., Muhlert, N., Pindus, D. M., Butler, C. R., Kapur, N., Graham, K. S., & Zeman,

A. Z. (2010). Remote memory deficits in transient epileptic amnesia. 133. Brain: AJournal of Neurology 1368–1379.

O'Connor, M., Butters, N., Miliotis, P., Eslinger, P., & Cermak, L. S. (1992). Thedissociation of anterograde and retrograde amnesia in a patient with herpesencephalitis. Journal of Clinical and Experimental Neuropsychology, 14, 159–178.

C.N. Smith et al. / Neuropsychologia 51 (2013) 2709–27142713

http://dx.doi.org/10.1016/j.neuropsychologia.2013.09.015http://dx.doi.org/10.1016/j.neuropsychologia.2013.09.015http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref1http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref1http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref2http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref2http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref3http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref3http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref4http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref4http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref4http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref5http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref5http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref6http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref6http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref7http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref7http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref8http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref8http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref8http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref8http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref9http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref9http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref9http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref9http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref10http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref10http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref10http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref10http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref10http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref11http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref11http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref12http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref12http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref13http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref13http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref13http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref14http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref14http://dx.doi.org/10.1002/hbm.22170http://dx.doi.org/10.1002/hbm.22170http://dx.doi.org/10.1002/hbm.22170http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref16http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref16http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref17http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref17http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref17http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref18http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref18http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref19http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref19http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref19http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref19http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref20http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref20http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref20http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref21http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref21http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref21http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref21http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref22http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref22http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref23http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref23http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref24http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref24http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref24http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref25http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref25http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref26http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref26http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref26http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref26http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref27http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref27http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref28http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref28http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref28http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref29http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref29http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref29http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref30http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref30http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref31http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref31http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref32http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref32http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref32http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref33http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref33http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref34http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref34http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref35http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref35http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref35http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref36http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref37http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref37http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref37http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref37http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref38http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref38http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref38

Osterrieth, P. A. (1944). Le test de copie d'une figure complexe [The test of copying acomplex figure]. Archives de Psychologie, 30, 206–356.

Reed, J. M., & Squire, L. R. (1998). Retrograde amnesia for facts and events: Findingsfrom four new cases. Journal of Neuroscience, 18, 3943–3954.

Rempel-Clower, N. L., Zola, S. M., Squire, L. R., & Amaral, D. G. (1996). Three cases ofenduring memory impairment after bilateral damage limited to the hippo-campal formation. Journal of Neuroscience, 16(16), 5233–5255.

Ribot, T. (1881). Les Maladies de la Memoire [English translation: Diseases of Memory].New York: Appleton-Century-Crofts.

Rose, F. C., & Symonds, C. P. (1960). Persistent memory defect following encepha-litis. Brain, 83, 195–212.

Russell, W. R. (1971). The traumatic amnesias. Oxford: Oxford University Press.Russell, W. R., & Nathan, P. W. (1946). Traumatic amnesia. Brain, 69, 280–300.Sanders, H. I., & Warrington, D. K. (1971). Memory for remote events in amnesic

patients. Brain, 94, 661–668.Sehm, B., Frisch, S., Thone-Otto, A., Horstmann, A., Villringer, A., & Obrig, H. (2011).

Focal retrograde amnesia: Voxel-based morphometry findings in a case withoutMRI lesions. PLoS One, 6(10), e26538.

Shuttleworth, E. C., & Morris, C. E. (1966). The transient global amnesia syndrome. Adefect in the second stage of memory in man. Archives of Neurology, 15(5),515–520.

Squire, L. R. (1974). Remote memory as affected by aging. Neuropsychologia, 12,429–435.

Squire, L. R., & Alvarez, P. (1995). Retrograde amnesia and memory consolidation: Aneurobiological perspective. Current Opinion in Neurobiology, 5, 169–177.

Squire, L. R., & Chace, P. M. (1975). Memory functions six to nine months afterelectroconvulsive therapy. Archives of General Psychiatry, 32, 1557–1564.

Squire, L. R., & Shimamura, A. P. (1986). Characterizing amnesic patients forneurobehavioral study. Behavioral Neuroscience, 100, 866–877.

Squire, L. R., Slater, P. C., & Miller, P. L. (1981). Retrograde amnesia and bilateralelectroconvulsive therapy. Long-term follow-up. Archives of General Psychiatry,38(1), 89–95.

Squire, L. R., Haist, F., & Shimamura, A. P. (1989). The neurology of memory:Quantitative assessment of retrograde amnesia in two groups of amnesicpatients. Journal of Neuroscience, 9, 828–839.

Taylor, L. B. (1998). Scoring criteria for the Rey-Osterrieth complex figure test. In:O. Spreen, & E. Strauss (Eds.), A compendium of neuropsychological tests.Administration, norms, and commentary (pp. 350–351). New York: OxfordUniversity Press.

Victor, M. (1969). The amnesic syndrome and its anatomical basis. Canadian MedicalAssociation Journal, 100(24), 1115–1125.

Victor, M., Adams, R. D., & Collins, G. H. (1989). The Wernicke–Korsakoff syndromeand related neurological disorders due to alcoholism and malnutrition (2nd ed.).Philadelphia: F.A. Davis.

Wickelgren, W. A. (1979). Chunking and consolidation: A theoretical synthesis ofsemantic networks, configuring, S–R versus cognitive learning, normal forget-ting, the amnesic syndrome, and the hippocampal arousal system. PsychologicalReview, 86, 44–60.

Zeman, A. Z., Boniface, S. J., & Hodges, J. R. (1998). Transient epileptic amnesia: Adescription of the clinical and neuropsychological features in 10 cases and areview of the literature. Journal of Neurology, Neurosurgery, and Psychiatry, 64(4), 435–443.

Zola-Morgan, S., Squire, L. R., & Amaral, D. G. (1986). Human amnesia and themedial temporal region: Enduring memory impairment following a bilaterallesion limited to field CA1 of the hippocampus. Journal of Neuroscience, 6,2950–2967.

C.N. Smith et al. / Neuropsychologia 51 (2013) 2709–27142714

http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref39http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref39http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref40http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref40http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref41http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref41http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref41http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref42http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref42http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref43http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref43http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref44http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref45http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref46http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref46http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref47http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref47http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref47http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref48http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref48http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref48http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref49http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref49http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref50http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref50http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref51http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref51http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref52http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref52http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref53http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref53http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref53http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref54http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref54http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref54http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref55http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref55http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref55http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref55http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref56http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref56http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref57http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref57http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref57http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref58http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref58http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref58http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref58http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref59http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref59http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref59http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref59http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref60http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref60http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref60http://refhub.elsevier.com/S0028-3932(13)00299-6/sbref60

Supplemental Material Figure S1

Figure Captions Figure S1. Series of eight T1-weighted coronal images of six patients are illustrated with limited hippocampal lesions (GW, JRW, KE, LJ, and RS), one patient with extensive medial temporal lobe damage (GP), and one control (CON). The sections proceed posteriorly in 7mm intervals from the temporopolar (TP) cortex in the top section. The left side of the brain is on the right side of each image. As described by Insausti et al. (1998), TP cortex extends medially from the inferotemporal sulcus (ITS) to the fundus of the TP sulcus. TP cortex extends rostrally from the tip of the temporal pole caudally to the limen insula (LI), which approximates the border between the TP cortex and perirhinal cortex (PRC). Caudal to TP cortex, the collateral sulcus (CS) is the most important structure for the identification of medial temporal lobe cortices. At its most rostral extent, the CS is surrounded entirely by PRC. Caudally, entorhinal cortex (EC) extends from the midpoint of the medial bank of the CS to the subiculum, while PRC extends laterally from the midpoint of the medial bank of the CS to the inferotemporal cortex. Two millimeters caudal to the disappearance of the gyrus intralimbicus of the hippocampus (H), the CS is surrounded by parahippocampal cortex (PHC). The caudal border of the posterior PHC is defined as lying 1.5mm posterior to the crus of the fornix at the point where the fimbria turns upwards to continue as the posterior pillars of the fornix and posterior to the pulvinar nucleus of the thalamus (Franko et al., 2012). The top section (1) shows the TP cortex and the ITS in the control brain. None of the patients with limited hippocampal lesions have damage evident at this level. For GP, the TP cortex is missing. The ITS is visible bilaterally at this level for patients GW, JRW, KE, and RS. For LJ, only the right ITS is visible. The second section (2) shows TP cortex and the ITS in the control brain. The ITS and TP cortex is evident in all patients with limited hippocampal lesions at this level. None of the patients with limited hippocampal lesions has damage evident at this level. For GP, note that the portion of the temporal lobe missing corresponds to TP cortex and involves the lateral temporal lobe to a minimal extent (~10%). The CS is visible, indicating the beginning of PRC, in patients KE and RS (right side only). The third section (3) shows the CS and surrounding PRC and EC in the control brain. None of the patients with limited hippocampal lesions have damage evident at this level with the exception of KE, who has damage in the basal ganglia secondary to toxic shock syndrome (and to a lesser extent in section 4). For patients GW, KE, and LJ, the PRC is evident on the left side, bounded by the LI and CS. On the right side, both EC and PRC are evident. For patients JRW and RS, both EC and PRC are evident bilaterally. For GP, no CS or surrounding tissue is evident. The fourth section (4) shows the anterior hippocampus and the adjacent PRC and EC in the control brain. The hippocampus is not yet visible at this level in any of the other patients with limited hippocampal lesions. No damage to the PRC or EC is evident for any of the patients at this level, except for GP who has no medial temporal lobe tissue at this level. The fifth section (5) shows the hippocampus and the adjacent PRC and EC in the control brain. The CS and the surrounding PRC and EC appear normal in all patients at this level with the exception of GP, who has no medial temporal lobe tissue at this level. Damage is evident in the hippocampal region of all patients. The sixth section (6) shows the hippocampus and the adjacent PRC and EC in the control brain. Damage is evident in the hippocampal region for all patients at this level. The surrounding PRC and EC appear normal in all patients except GP, who has little normal medial temporal lobe tissue in either hemisphere. Both the PRC and EC are visible in all hippocampal patients bilaterally, with the exception of JRW for whom only PRC is visible on the left side, indicated by the disappearance of the gyrus intralimbicus 2 mm rostral to the sixth section (not shown). The seventh section (7) shows the hippocampus and the CS, surrounded by PHC in the control brain. Damage to the hippocampus is evident in all patients at this level. In all patients with damage limited to the hippocampus, the PHC is evident. Patient GP has little normal medial temporal lobe tissue in either hemisphere. The eighth section (8) shows the hippocampus in the control brain. Bilateral hippocampal damage is evident in patients GW, KE, and GP at this level. Patient

LJ shows hippocampal damage only on the left side, and no damage is evident in patient RS. At this level, the hippocampus is no longer evident in patient JRW. PHC is no longer evident at this level in patients JRW, KE, LJ, or RS and PHC appears normal in patient GW. Patient GP has some spared PHC on the right at this level. The warping artifact in the right lateral temporal lobe of GW on this section did not interfere with the assessment of his damage. Posterior to this level, GP exhibits hippocampal damage and damage to the PHC. No damage is evident posterior to this level for any of the other patients.

Figure S2. The relationship between the severity of anterograde amnesia (AA) and the severity of retrograde amnesia (RA) in 11 patients with bilateral damage to the medial temporal lobe. Patients are represented by their initials (see Table 1). AA is the mean z-score from five tests of new learning ability (see section 2.2). RA was measured by a test of approximately 100 questions about notable news events that covered most of the lifespan prior to the onset of amnesia. A. The severity of RA was estimated by calculating each patient’s mean percent correct score across the entire test(r = 0.73, p < 0.05). B. The severity of RA was estimated by calculating each patient’s mean percent correct score across the entire test and then converting the percent correct score to a z-score (r = 0.79, p < 0.01). Figure S3. The relationship between the severity of anterograde amnesia (AA) and the severity of retrograde amnesia (RA) in 10 patients with bilateral damage to the medial temporal lobe. Patients are represented by their initials (see Table 1). RA was measured by a test of approximately 100 questions about notable news events that covered most of the lifespan prior to the onset of amnesia. The extent of RA was measured in 5-year intervals (see section 2.3). A. AA is the mean percent correct score for questions about news events that occurred after the onset of amnesia (r = 0.73, p < 0.05). B. AA was estimated by calculating each patient’s mean percent correct score for questions about news events that occurred after the onset of amnesia. This score was then converted to a z-score (r = 0.59, p < 0.08). Figure S4. The relationship between the severity of anterograde amnesia (AA) and the severity of retrograde amnesia (RA) in 10 patients with bilateral damage to the medial temporal lobe. Patients are represented by their initials (see Table 1). AA was estimated by calculating each patient’s mean percent correct score for questions about news events that occurred after the onset of amnesia. This score was then converted to a z-score. RA was measured by a test of approximately 100 questions about notable news events that covered most of the lifespan prior to the onset of amnesia. A. The severity of RA was estimated by calculating each patient’s mean percent correct score across the entire test (r = 0.89, p < 0.001). B. The severity of RA was estimated by calculating each patient’s mean percent correct score across the entire test and then converting the percent correct score to a z-score (r = 0.86, p < 0.01).

References

Franko E, Insausti AM, Artacho-Perula E, Insausti R, Chavoix C. 2012. Identification of the human medial temporal lobe regions on magnetic resonance images. Hum. Brain. Mapp.doi: 10.1002/hbm.22170 Insausti R, Juottonen K, Soininen H, Insausti AM, Partanen K, Vainio P, Laakso MP, Pitkanen A. 1998. MR volumetric analysis of the human entorhinal, perirhinal, and temporopolar cortices. Am. J. Neuroradiol. 19:659-671.

489_Smith_etal_Neuropsy_2013The nature of anterograde and retrograde memory impairment after damage to the medial temporal lobeIntroductionMaterials and methodsParticipantsMeasuring anterograde amnesiaDelayed recall of a complex figurePaired-associate learningRey auditory verbal learning test (RAVLT)Dementia rating scaleWechsler memory scale-revised (WMS-R) logical memory subtest

Measuring retrograde amnesia

ResultsDiscussionAcknowledgmentsSupplementary MaterialReferences

489a_Smith_etal_Neuropsy_2013_SuppSupplemental MaterialFigure S1Figure S1. Series of eight T1-weighted coronal images of six patients are illustrated with limited hippocampal lesions (GW, JRW, KE, LJ, and RS), one patient with extensive medial temporal lobe damage (GP), and one control (CON). The sections proceed...As described by Insausti et al. (1998), TP cortex extends medially from the inferotemporal sulcus (ITS) to the fundus of the TP sulcus. TP cortex extends rostrally from the tip of the temporal pole caudally to the limen insula (LI), which approximat...The top section (1) shows the TP cortex and the ITS in the control brain. None of the patients with limited hippocampal lesions have damage evident at this level. For GP, the TP cortex is missing. The ITS is visible bilaterally at this level for pat...